Who’s to blame? These three scientists are at the heart of the Surgisphere COVID-19 scandal


E. PETERSEN/SCIENCE

By Charles Piller Jun. 8, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.

Three unlikely collaborators are at the heart of the fast-moving COVID-19 research scandal, which led to retractions last week by The Lancet and The New England Journal of Medicine (NEJM), and the withdrawal of an online preprint, after the trove of patient data they all relied on was challenged. The three physician-scientists never were at the same institution nor had they ever before written together, but they are the only authors in common on the disputed papers, and the other co-authors all have ties to at least one of them. Their partnership, which seized a high-impact role during a global public health crisis, has now ended disastrously.

The first author for both retracted papers was cardiac surgeon Mandeep Mehra, an eminent Harvard University professor who works at Brigham and Women’s Hospital (BWH) and is known internationally for cardiovascular medicine and heart transplants. He provided the kind of gravitas that can fast-track papers to leading journals. In a statement provided by BWH, Mehra said he had met another of the trio, cardiac surgeon Amit Patel, in “academic and medical circles,” and that Patel had introduced him to Sapan Desai, a vascular surgeon and founder of Surgisphere, the tiny company that supplied the data. Journal disclosures, however, also indicate Mehra received compensation from Triple-Gene, a gene therapy company Patel co-founded to develop cardiovascular treatments.
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Desai publicly aspired to combine big data and artificial intelligence (AI) in ways that he said can replace randomized controlled clinical trials. For a brief moment, it seemed that Surgisphere’s enticing data set, said to include nearly 100,000 detailed patient records from about 700 hospitals on six continents, would settle questions about the possible benefits of various drugs—including the controversial antimalarial hydroxychloroquine—for COVID-19 patients.

Patel once apparently headed cardiac surgery at the University of Miami Miller School of Medicine. A university press release announcing his arrival in 2016 is no longer posted on the university website, however, and the school has not confirmed his job duties there. More recently, he has been a volunteer adjunct professor at the University of Utah. But, as STAT first reported yesterday, Patel tweeted on Friday that he had severed his relationship with the university, which a school spokesperson confirmed. In recent years Patel has developed and commercialized experimental stem cell therapies purported to cure heart problems, reverse aging, or treat sexual dysfunction. He is also part of a network of physicians that just launched a trial to use stem cells from umbilical cord blood to treat COVID-19 patients.

Normally co-authors of high-profile papers share subject area expertise or have clear professional ties, says Jerome Kassirer, chief editor of NEJM during the 1990s. He calls the collaboration of the apparently disparate individuals “completely bizarre,” and a red flag that the studies warranted intensive scrutiny that the journals failed to provide.

None of the three co-authors responded to requests for comment. Patel spoke with a Science reporter initially but said he wanted to wait for audits of the Surgisphere data to comment, and Desai’s spokesperson stopped communicating after the retractions. Still, interviews with former colleagues and a long paper trail shed some light on each of them.
Sapan Desai

Desai had a history of convincing respected researchers of his skill and integrity. One of them, Gilbert Upchurch, department of surgery chair at the University of Florida, wrote last year in a journal commentary that he had only brief encounters with Desai but had nonetheless mentored him remotely and developed an online friendship with him. Upchurch placed the scientist in a group of “amazing and talented young vascular surgeons.”




Sapan Desai SOUTHERN ILLINOIS UNIVERSITY SCHOOL OF MEDICINE

Illinois court records show Desai is facing two medical malpractice lawsuits filed last year. He told The Scientist that he “deems any lawsuit naming him to be unfounded.”

Desai has a history of big aspirations and entrepreneurial ventures—some short-lived. His science-fiction blog, corewardfront.com, was meant “to find the most parsimonious route for mankind to establish a meaningful presence in space.” In 2009, he wrote that the site would publish fiction “grounded in facts and reality,” adding, “the scientific method must be followed … religiously.” The blog is no longer published.

As a student, Desai won several small National Institutes of Health (NIH) grants for studies of the vestibular system. He started Surgisphere in 2007, when he was a medical resident at Duke University. Surgisphere’s initial products were medical guides and textbooks, although Desai has said he was working on big data projects for the company from its birth. In 2010, under the firm’s auspices, he founded the Journal of Surgical Radiology—whose editors included researchers with well-established publishing records. It folded in January 2013. Articles from the journal were cited only 29 times in its history, according to Scimago, a journal rating service. Yet an undated Surgisphere web page, no longer accessible online, said the online-only publication had 50,000 subscribers and nearly 1 million page views monthly—which would have placed it in elite company in academic publishing.

Surgisphere appears over time to have shifted its efforts into developing a database of hospital records that could be used for research. When the pandemic erupted, Desai declared that his data set could answer key questions about the efficacy and safety of treatments. Speaking about the finding that hydroxychloroquine increases mortality in COVID-19 patients, the main finding from the now retracted Lancet paper, he told a Turkish TV reporter, “with data like this, do we even need a randomized controlled trial?” Soon after, the World Health Organization temporarily suspended enrolling patients for its COVID-19 trial of the drug.

Immediately after the Lancet and NEJM studies appeared, however, critics identified anomalies in the data. And they doubted that a tiny firm—with a scant public track record in AI, few employees, and no publicly named scientific board—could convince hundreds of unidentified hospitals in dozens of nations to share complex, protected, and legally fraught patient data. Ultimately, despite Desai promising repeatedly to allow an independent audit of Surgisphere, the firm refused to release the raw patient data and agreements with hospitals for an audit, so no one could validate the authenticity of its database.

No hospitals have come forward to acknowledge working with Surgisphere. Indeed, NHS Scotland, which is mentioned as a case study on the company’s website, says none of its hospitals worked with Surgisphere and that it would ask the firm to remove an image of a Glasgow hospital from its website.

Science contacted several of Desai’s current or former employees or colleagues. Most would not comment. But Fred Rahimi, an Illinois podiatrist and co-author of a paper with Desai, praises the surgeon as highly capable for salvaging limbs, and easy to work with. Through his publicist, Desai cited Mark Melin, a University of Minnesota, Twin Cities, vascular surgeon, as a supporter. Before the retractions, Melin called Desai “a gentleman of the highest integrity” who has “nothing to cover up.”

But one physician-scientist who worked closely with Desai several years ago, says, “Just about everyone who knew him would say: ‘I just didn’t have a good feeling about him.’ … After they’d been with him, most people dissociated themselves from him,” the scientist says, declining to be named to avoid personal and institutional embarrassment.

In the decade since completing his medical residency, Desai moved from job to job—at Duke, the University of Texas, Southern Illinois University, and two private Illinois hospitals, according to his LinkedIn profile. “You might say we should have stopped him, which now seems obvious,” Desai’s former colleague says. “We should have found a way to get together and say, ‘What’s going on here?’ rather than allowing him to move from place to place. We should have done better as a medical community. We looked the other way.”
Amit Patel

Before and after his stint at the University of Miami, which appears to have started in late 2016 or early 2017, Patel’s academic home was the University of Utah. He started as a full-time faculty member at Utah in 2008 and kept that position until he left for Miami. The website for Foldax, a heart valve company that he serves as medical adviser, describes him as a “Tenured Professor of Surgery in the Division of Cardiothoracic Surgery at the University of Utah School of Medicine and Director of Clinical Regenerative Medicine and Tissue Engineering at the University of Utah.”




Amit Patel LAURA SEITZ/DESERET NEWS

The university confirmed Patel had tenure there, but says the directorship was an “unofficial title.” And among more than 100 publications listed on his University of Utah profile, nearly two-thirds were actually co-authored by other scientists who share the same surname. The page was removed from the university website after inquiries from Science. A university spokesperson said the timing, late Friday last week, was when Patel and the school agreed to separate.

According to the NIH database, Patel has never received funding from the agency. Before the recent COVID-19 papers, one of his most notable publications was a 2016 paper in The Lancet, which reported that extracting stem cells from the bone marrow of a person with end-stage heart failure and then reinjecting them could reduce the number of cardiac events that produced deaths or hospital admissions by 37%. The 126 patient, 31-site, phase II trial was billed in a press release, now not available on the University of Utah website but stored elsewhere, as “the largest cell therapy trial for heart failure to date.” Despite the apparent positive results, the sponsoring company Vericel no longer is developing stem cells for heart disease and, according to its webpage, is focused on “advanced cell therapies for the sports medicine and severe burn care markets.”

Patel left Miami under unclear circumstances, but has retained ties with Camillo Ricordi, an influential stem cell researcher at the University of Miami School of Medicine who is also the founder of a nonprofit called the Cure Alliance. The alliance previously focused on testing whether stem cells derived from umbilical cord blood could treat diabetes or Alzheimer’s, but has now pivoted to “fighting COVID-19,” according to its website. Ricordi is the principal investigator on a multisite trial to see whether the stem cells can treat lung inflammation in severe COVID-19 patients and Patel is listed in various references to the trial as a “key contributor” or “co–principal investigator.” Ricordi says Patel is an upaid collaborater on the trial and praises Patel's work in regenerative medicine.

Patel recently tweeted that he is “related to Dr. Desai by marriage” but called that “old news” and added, “Despite this I still do not have the information of what happened at Surgisphere.” In addition to apparently connecting Mehra and Desai, Patel had prior connections with other authors of the NEJM paper and the preprint. David Grainger, co-author of the preprint, is a professor of biomedical engineering at the University of Utah and also works with Foldax. Grainger declined to comment.

Timothy Henry, a cardiovascular clinician and scientist at the Christ Hospital in Cincinnati and a co-author on the NEJM article, has written several scholarly articles with Patel, including the 2016 Lancet paper. Henry, who also declined to comment, advises Patel’s Triple-Gene, which develops cardiovascular gene therapy treatments. Henry and Patel advise—and Patel is a board member of—Creative Medical Technology Holdings, a Phoenix company that develops and markets stem cell therapies, including treatments purported to reverse aging and cure sexual disfunction.

Creative Medical’s CaverStem and FemCelz kits are distributed to physicians who use them to extract stem cells from a patient’s bone marrow, then inject the cells into the penis or clitoral area to stimulate blood flow, according to a statement filed with the U.S. Securities and Exchange Commission. (As of the market close Friday, the publicly traded firm’s shares were valued at one-third of 1 cent.) The CaverStem treatments are advertised by the company as successful in more than 80% of patients, based on a 40-person phase I clinical trial that was not randomized or controlled, and on observations of 100 other patients. Phase I trials typically measure safety, not health benefits of a potential treatment.

Science contacted multiple colleagues or co-authors of Patel. None would comment. Before the retractions, two high-profile researchers—Deepak Bhatt, who directs interventional cardiovascular programs at BWH; and Peter Gruber, a pediatric cardiothoracic surgeon at Yale University—endorsed Patel on his LinkedIn page. Bhatt says he doesn’t know Patel and attempted to remove his endorsement after being contacted by Science. Gruber says he overlapped with Patel at the University of Utah about a decade ago, but doesn’t know his work in detail.
Mandeep Mehra

In contrast, Mehra—author of more than 200 scholarly articles, editor of The Journal of Heart and Lung Transplantation, and head of the cardiology division of the University of Maryland before moving to BWH in 2012—enjoys considerable support even after the unraveling of the recent studies. “Obviously, you don’t rise to the position he’s risen to without being ambitious, but I’ve never had any indication whatsoever that he would do anything unethical,” says Keith Aaronson, a cardiologist at the University of Michigan, Ann Arbor, who collaborated with Mehra on several studies, including a clinical trial of a mechanical pump for heart failure patients.




Mandeep Mehra © STU ROSNER

Mehra, the first author on both retracted papers, was the only one to issue a personal statement of apology, for failing “to ensure that the data source was appropriate for this use.” BWH and Harvard declined to say whether further investigation of Mehra’s roles in the papers would occur. (Mehra has written papers recently with another co-author of the Lancet paper, Frank Ruschitzka of University Hospital Zürich.)

“I think he just fell into this—perhaps a little naïvely,” says another former collaborator, cardiothoracic surgeon Daniel Goldstein of the Albert Einstein College of Medicine. “Given the amount of data that was in the [Surgisphere] database, it’s just hard to believe someone would [fabricate] something like this.”

Kassirer offers a harsher view: “If you’re a scientist and you’re going to sign on to a project, by God you should know what the data are.”

With reporting by Kelly Servick and John Travis.

This story was supported by the Science Fund for Investigative Reporting.
Posted in:
Health
Scientific Community
Coronavirus
Science Fund for Investigative Reporting

doi:10.1126/science.abd2252

Charles Piller
Charles is a contributing correspondent based in Oakland, California.

U.S. science groups wary of new Senate bills to curb foreign influences

U.S. science groups wary of new Senate bills to curb foreign influences

LOOKING FOR REDS UNDER THE BED
Senator Rob Portman (R–OH) has assembled a bipartisan coalition for his bill targeting foreign influences. SENATE TELEVISION VIA AP

By Jeffery Mervis Jun. 18, 2020

A bipartisan group of U.S. senators today proposed sweeping—and controversial—changes in how the federal government manages academic research in the face of threats from other countries.

The authors of the legislation, more than 1 year in the making, tout it as a way to stop China and other countries from stealing the fruits of federally funded research and using the information to damage U.S. economic and national security. But research advocates worry that if enacted, the bill could damage the U.S. academic research enterprise by restricting the flow of talent and ideas.

The legislation, which was drafted by Senators Rob Portman (R–OH) and Tom Carper (D–DE) and has eight Republican and five Democratic co-sponsors, is the latest, and most substantive, attempt in Congress to reconcile these competing interests. It would make a number of subtle but potentially significant changes in how the U.S. government keeps tabs on those who receive federal grants, who gets to enter the country to carry out research deemed sensitive to national interests, and how U.S. scientists interact with foreign partners.

One contentious provision would give the Department of State grounds to reject a visa application from anyone with ties to a foreign government seen as hostile to the United States. Other sections of the bill would expose scientists who fail to disclose ties to a foreign government to criminal penalties including jail time, require international partners to embrace U.S. scientific norms, and give the White House budget office new powers to oversee research security.

The legislators backing the bill say they recognize the need to strike a balance. But their rhetoric is anything but subtle. “For nearly 2 decades, the federal government has been asleep at the wheel while foreign governments have exploited the lack of transparency in our education system and bought access and influence on our school campuses,” says Portman, who leads the homeland security committee’s Permanent Subcommittee on Investigations (PSI), which has sharply criticized current federal efforts to tackle the problem.

Nor do the lawmakers hide their intended target. “America’s research enterprise is the best in the world and the Chinese Communist Party knows it,” says Senator Josh Hawley (R–MO). “That’s why they’ve spent the last 20 years stealing American taxpayer-funded intellectual property.”

Carper, the top Democrat on the panel, is a bit more judicious in his language, describing “the ways in which the Chinese government has worked to exploit the open and collaborative nature of the U.S. research community to advance their businesses and military interests.” He calls the bill a “common sense [approach] to protect American intellectual property and better leverage our international research partnerships.”

Unease among science groups

Science advocates acknowledge the need to protect U.S. interests, but they believe Portman’s bill goes too far in how it would police the research enterprise. “I don’t think the higher education community is going to like any of this,” says one science lobbyist, who like many advocates requested anonymity because they were not authorized to speak for their organization.

The Association of American Universities, a 66-member coalition of leading research institutions, said in a statement that it “shares Senators Portman and Carper’s goal of securing research conducted on our campuses, and universities are taking specific steps to address security concerns,” but “key provisions in the bill are overly broad and will only serve to harm American science without improving national security. … We appreciate that Sens. Portman and Carper have changed language in certain sections of the bill in response to concerns raised by our universities, but the breadth of the current bill language could still block talented students and scholars from coming to the U.S., where they advance our science and economic interests.”

One big sticking point is language giving the State Department the ability to reject a visa application from anyone based on their “cooperation with … military organizations adversarial to the United States, foreign institutions involved in the theft of United States research [or] a government that seeks to undermine the integrity and security of the United States research community.” Although the bill doesn’t name China, Portman and many other legislators believe its growth as a scientific superpower has been fueled by the widespread use of such tactics.

Lobbyists worry that, depending on how it is interpreted, the language has the potential to slam the door on the thousands of Chinese graduate students and postdocs who seek to study in the United States each year. The provision puts “no guard rails” on the State Department’s power, one lobbyist worries. “Every Chinese student has a direct connection to the government” and so could be viewed as persona non grata. The State Department already has criteria in place to exclude high-risk foreign applicants, the critics add, so it’s not clear why it needs broader powers.

PSI staffers say those fears are not warranted. They say the legislation gives the State Department authority it now lacks and has requested, to consider such factors as a visa applicant’s ties to military groups. Such ties are currently insufficient to exclude an applicant, they say. Instead, the bill would direct the State Department to “weigh the proportionality of risk” before deciding whether to issue a visa.

“The focus of the bill is on bad actors,” a staffer notes. “The vast majority of foreign researchers [asking to come to the United States] are benign, and we need their talents.”

The bill would also empower the State Department to reject or restrict the activities of a visa applicant if officials decide it would harm the country to give them access to “goods, technologies, or sensitive information.” The United States already has extensive rules governing the sharing and export of research products deemed sensitive. But lobbyists worry government officials could use the new provision to require universities to impose arbitrary restrictions on who could attend an open lecture, for example, or who could visit a laboratory that is doing unclassified research. “It violates the culture of openness that is fundamental to academic research,” one says.

PSI staffers believe the community is overreacting to what is simply a common-sense approach to research security in today’s globally competitive environment. “We’re not locking down campuses,” one says. But universities and other federally funded institutions “don’t need to give everyone access to everything.”

Using the budget hammer

The legislation would also lower the profile of an existing high-level intergovernmental panel that is tackling many of these issues. That panel, the Joint Committee on Research Environment (JCORE), was created last year by Kelvin Droegemeier, director of the White House Office of Science and Technology Policy (OSTP), to examine issues ranging from foreign influences to sexual harassment.

Its first product, expected out later this summer, is expected to be a proposed common federal policy relating to disclosing foreign sources of support. Nearly a score of research agencies has been working on the document. (Portman’s bill would criminalize the failure to disclose such ties, and would ban violators from receiving a federal grant for 5 years.)

The bill would make JCORE a working group of a new body, called the Federal Research Security Council, which would be led by the White House Office of Management and Budget (OMB). Lobbyists question giving that role to OMB. They say OMB has neither OSTP’s understanding of the research enterprise nor its strong connections to the scientific community. And they worry OMB’s purview is so broad that research could get lost among its many priorities.

PSI staffers say OMB’s clout is exactly why it was put in the driver’s seat. “We think that OSTP has been doing a great job. And giving OMB these powers is a good way to supercharge that effort,” one staffer says. As one example, staffer cite the role OMB could play in implementing the bill’s requirement that research agencies use a common grant application. “If one agency argues that it has unique needs, then OMB has the ability to step in and insist that it make concessions to reach an agreement.” OSTP, they suggest, couldn’t knock heads in the same way.
Gifts in the spotlight

Higher education organizations are also unhappy with a provision that lowers the requirement for reporting gifts, including grants, from another government or any foreign entity. The current standard is $250,000, and in the past year, the Department of Education has conducted investigations of several major universities that it says have ignored the rule. Universities say the government has never spelled out what it expects from institutions.

Portman’s bill throws gasoline on the simmering dispute by reducing the threshold to $50,000. University officials say the smaller amount negates the original purpose of the rule, which was designed to monitor attempts by foreign governments to influence such core academic activities as course offerings or the direction of faculty research.

“$50,000 is not enough to influence anything,” one official says. “And the additional reporting that would be required represents a significant administrative burden.”

Portman dismisses that criticism and doesn’t see the need to compromise. “There’s some in the university community that don’t love our legislation,” he said last month in a floor speech that outlined his pending bill. “I would just ask them, given what we know is happening in terms of the theft of U.S. research, are you really going to stand in the way of legislation that just says you have to report when you receive more than $50,000 from a foreign government? Is that too much to ask? I don’t think so.”

Whose values?

Another potential bone of contention for researchers is a provision that would require all U.S. international agreements to contain language requiring foreign partners “to adhere to U.S. scientific values.” On the surface, those values appear noncontroversial; they include “transparency, reciprocity, integrity, and merit-based competition.”

“If we expect U.S. federally funded researchers to be transparent, ensure the integrity of their work, make their work available to others to confirm, compete based on the merit of their work and not their seniority or rank, and share information with the scientific community, then we should hold U.S. federally funded projects involving foreign counterparts to the same standard,” a PSI staffer says.

But those principles are more nuanced than they appear, one lobbyist notes. For example, not every U.S agency uses “merit-based competition” for all grantmaking. Beyond that detail, the lobbyist notes, the attempt to require another country to follow U.S. “values” before partnering with U.S. scientists could be problematic for researchers overseas.

This and other sections of the original bill relating to international agreements were removed at the last minute and introduced as separate legislation. The move was taken to align the bills with the oversight authority of individual Senate committees. The main bill will be taken up by the homeland security panel that Portman chairs. The second piece goes before the Senate Committee on Foreign Relations.

So far there is no companion bill in the House of Representatives, although some members have introduced narrower measures aimed at curbing foreign influences on federally funded research. Congress watchers say such sweeping legislation would be harder to pass in the House because of jurisdictional issues as well as greater skepticism among its Democratic leaders that the problem warrants wholesale changes in federal oversight of research.

doi:10.1126/science.abd3887

‘Has it peaked? I don’t know.’ NIH official details foreign influence probe

The National Institutes of Health (main campus shown here) can take months to vet an allegation of undisclosed foreign ties. NATIONAL INSTITUTES OF HEALTH

By Jeffrey Mervis Jun. 22, 2020

Four years after the National Institutes of Health (NIH) began to investigate grantees who it believed had failed to disclose their ties to foreign governments, officials still don’t know the full extent of the problem.

“We’ve learned of 150 cases in the past 12 months,” says the head of NIH’s extramural research program, Michael Lauer, who oversees an ongoing probe that has swept up 399 scientists since NIH received the first allegation in June 2016. “But has it peaked, and will we have the same number of new cases over the next 12 months? I just don’t know.”

On 12 June, Lauer offered the fullest analysis to date of the pool of scientists NIH has been investigating and the nature of their offenses. But the data left many questions unanswered. Last week, Lauer fleshed out that analysis during an interview with ScienceInsider, offering new details on the scope of NIH’s investigation and how it fits into the larger debate now roiling Congress over how to prevent other countries from acquiring federally funded research in ways that threaten U.S. economic and national security.

Since July 2018, Lauer says, NIH has sent letters to 87 institutions raising questions about the behavior of 189 scientists. That group is a subset of the 399 grantees who have so far come to NIH’s attention, Lauer explained. Of those 399 scientists, he says, NIH determined that 251 warranted further scrutiny. NIH has since exonerated 76 scientists; 72 cases are still pending.
Lost jobs

Within the group of 189, 54 have subsequently lost their jobs. (NIH has declined to make their names public, although media reports have described and identified roughly two dozen scientists who appear to fall into that category.)

Asked why they were fired or dismissed, Lauer says the decisions were made by their institutions, not by NIH. “We do not render an opinion on HR [human resources] matters,” he says.

He notes that 70 of the 189 scientists were found to have violated rules at their institution, most notably a ban on receiving outside support for their research without prior approval from their employer. (In 93% of the 189 cases, the funding came from China, and the vast majority of the scientists under scrutiny are Asian men in their 50s.)

Lauer emphasized that NIH is examining only a narrow slice of the broader issue of inappropriate or illegal activity involving foreign sources of funding. “We focus on grant noncompliance,” he says, referring to a long-standing NIH policy that grantees must disclose material support for their research from any outside source.

The data Lauer presented are in line with that explanation. Of the 189 scientists flagged in its letters to institutions, 133 of them (70%) failed to disclose a grant from a foreign entity, and 102 failed to disclose their participation in a foreign talent recruitment program, such as China’s Thousand Talents Program.


Michael Lauer oversees the National Institute of Health’s review. NATIONAL INSTITUTES OF HEALTH

Cases involving the alleged theft of intellectual property or economic espionage, he says, are referred to either the inspector general for NIH’s parent body, the Department of Health and Human Services, or to the Department of Justice (DOJ). DOJ’s China Initiative, launched in November 2018, has led to the arrests of several scientists, including biochemist Charles Lieber of Harvard University.

Although the U.S. government asserts that many of them have helped the Chinese government illegally acquire U.S. technology, they are typically charged with other offenses, such as lying to the Federal Bureau of Investiation (FBI). Lauer’s data show a relative handful of the 189 scientists tagged appeared to be active in commercializing their research: Only 17 had hidden their involvement with a foreign company, for example, and seven had failed to tell NIH about a foreign patent.
Few mistakes claimed

Investigating alleged nondisclosure by an NIH grantee is a very labor-intensive process that can take “as long as several months,” Lauer says. It encompasses looking for mentions of foreign ties and grants in published papers, press releases, and other public descriptions of their research activities. Although NIH’s own sleuthing accounts for the majority of the workload, FBI did the initial legwork in some 30% of the 399 cases, according to Lauer’s data. In 11% of the cases, the scientist’s own institution contacted NIH with concerns.

Lauer says NIH is rarely wrong once it decides an NIH-funded scientist is likely to have violated its policies on disclosure. The data he presented on 12 June show 71% of the 87 institutions that received letters “acknowledged noncompliance.” He says there are additional cases in which an institution took action without admitting liability. He cited, for example, a December 2019 settlement between DOJ and the Van Andel Research Institute, in which the institute agreed to repay NIH $5.5 million in a case involving two scientists that had received funding from the Chinese government.

“They claimed that because the [Chinese] research did not overlap with what we were funding, they had no obligation to report it to us,” Lauer says. “But that is false,” he asserts.

“Of course, an institution has the right to disagree with us,” Lauer says. But he estimates that there are “fewer than 10 cases” in which institutions persuaded NIH that it had erred in claiming a grant recipient had violated the agency’s policy on disclosure.
Posted in:
Science and Policy
Scientific Community

doi:10.1126/science.abd4593

Fifty-four scientists have lost their jobs as a result of NIH probe into foreign ties


The National Institutes of Health has been investigating grantees suspected of not disclosing their links to foreign institutions, notably in China. NATIONAL INSTITUTES OF HEALTH

By Jeffrey Mervis Jun. 12, 2020

Some 54 scientists have resigned or been fired as a result of an ongoing investigation by the National Institutes of Health into the failure of NIH grantees to disclose financial ties to foreign governments. For 93% of the 189 scientists whom NIH has investigated to date, China was the source of their undisclosed support.

The new numbers come from Michael Lauer, NIH’s head of extramural research. Lauer had previously provided some information on the scope of NIH’s investigation, which had targeted 189 scientists at 87 institutions. But his presentation today to a senior advisory panel offered by far the most detailed breakout of an effort NIH launched in August 2018 that has roiled the U.S. biomedical community, and resulted in criminal charges against some prominent researchers, including Charles Lieber, chair of Harvard University’s department of chemistry and chemical biology.

“It’s not what we had hoped, and it’s not a fun task,” NIH Director Francis Collins said in characterizing the ongoing investigation. He called the data “sobering.”

In the vast majority of cases, Lauer reported, the person being investigated has been an Asian man in his 50s. Some three-quarters of those under investigation had active NIH grants, and nearly half had at least two grants. The 285 active grants totaled $164 million.

Lauer also presented data on the nature of the violations that NIH has uncovered. Some 70% (133) of the researchers had failed to disclose to NIH the receipt of a foreign grant, and 54% had failed to disclose participation in a foreign talent program. In contrast, Lauer said, only 9% hid ties to a foreign company, and only 4% had an undisclosed foreign patent. Some 5% of cases involved a violation of NIH’s peer-review system.

Lauer said the fact that 82% of those being investigated are Asian “is not surprising” because “that’s who the Chinese target” in their foreign talent recruitment programs. Some 82% are men, and their median age is 56, with the youngest being 48 and the oldest 59. Slightly more than one-half had been an NIH peer reviewer in the past 2 years, and 41% of those under investigation (77 scientists) have been barred by their institutions from submitting a grant proposal to NIH or serving as a principal investigator on an NIH award.

NIH has been in the forefront of federal efforts to identify and block behavior that many U.S. government officials say poses a significant threat to the country’s economic well-being and to national security. Several bills pending in Congress seek to limit that threat in various ways, including by limiting the flow of scientific talent from China to the United States, and by restricting access to federally funded research that provides a foundation for cutting-edge technologies and new industries.

Lauer’s presentation also provided a glimpse into the scope of that broader investigation. There are 399 scientists “of possible concern” to NIH, he told the advisory council, and the Federal Bureau of Investigation has fingered 30% (121) of them. An additional 44 have been flagged by their own institutions. Of that pool, Lauer said, investigations into 63%, or 256 scientists, came out “positive.” Investigations into some 19% came up “negative,” he noted, whereas the status of the remaining 18% is “pending.”

*Correction, 19 June, 1:15 p.m.: This story has been revised to clarify the pool of scientists who have failed to disclose financial support from foreign sources and the actions that their institutions have taken.
Posted in:
Scientific Community

doi:10.1126/science.abd308

‘It’s a nightmare.’ How Brazilian scientists became ensnared in chloroquine politics


The Nossa Senhora Aparecida cemetery in Manaus, Brazil, where many COVID-19 victims are buried. The city’s clinical trial with chloroquine started in late March, when cases had begun to explode. MICHAEL DANTAS/AFP VIA GETTY IMAGES

‘It’s a nightmare.’ How Brazilian scientists became ensnared in chloroquine politics

By Lindzi Wessel Jun. 22, 2020

Science’s COVID-19 reporting is supported by the Pulitzer Center.

Now that several big trials have shown disappointing results, hope has faded that chloroquine or hydroxychloroquine might be miracle drugs against COVID-19. But for one group of researchers in Brazil, the story is far from over.

In April, a team led by Marcus Lacerda, a clinical researcher at the Heitor Vieira Dourado Tropical Medicine Foundation in Manaus, Brazil, published a study showing chloroquine can increase mortality in COVID-19 patients. Since then, they have been accused of poisoning their patients with a high dose of chloroquine just to give the drug—praised by U.S. President Donald Trump and his Brazilian counterpart Jair Bolsonaro—a bad name. Social media attacks, defamatory articles, death threats, and even a legal inquiry into the group’s work have left Lacerda and his team stressed and exhausted.
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Other scientists have watched the public spectacle with dismay. But some agree that about half of the patients in the trial received such a high dose that severe side effects, or even deaths, were not unexpected. Lacerda’s trial was one of several using doses that were “dangerous and definitely too high,” says Peter Kremsner of the University of Tübingen in Germany, who is using far lower doses in two trials of hydroxychloroquine. Others say Lacerda and his colleagues took a calculated risk at a time when the optimal dose for SARS-CoV-2, the virus that causes COVID-19, was still under debate. “It’s clearer now that you wouldn’t have gone for that dose,” says Nicholas White, a veteran malaria researcher at Mahidol University in Bangkok who helped design the Recovery trial in the United Kingdom, which included a hydroxychloroquine arm. “But at that time, I think it was a legitimate choice.”
‘Left-wing medical activists’

Lacerda started the trial in late March, at a time when coronavirus cases in Manaus were growing explosively and scientists had promising results from chloroquine and hydroxycholoroquine in test tube studies and small, nonrandomized clinical studies. (Lacerda chose chloroquine because it’s widely available as a malaria treatment in Brazil.) The plan was to recruit 440 patients and give half of them 600 milligrams (mg) of chloroquine twice a day over a 10-day period—a total of 12 grams. The other half received 900 mg for 1 day followed by 450 mg for 4 days, a total of 2.7 grams.

When the trial’s independent data safety monitoring team saw the number of deaths in the high-dose group rise rapidly, they alerted the researchers and asked for that arm to be stopped. Of 81 patients enrolled at the time, seven in the high-dose group had died, versus four in the low-dose group. By the times the results were published, those numbers had risen to 16 and six, respectively. Two patients from the high-dose group developed dangerous cardiac arrhythmias before death, a known side effect from chloroquine, and warning signs for future heart trouble were more common in the high-dose group. An 11 April preprint about the results was covered by international media outlets, including The New York Times.

On 14 April, Michael James Coudrey, CEO of a U.S. marketing company whose website says he offers “social media and ‘digital information warfare’ services to political candidates,” tweeted accusations that the researchers had overdosed their patients and used them as “guinea pigs” in a study conducted “so irresponsibility I can’t even believe it.” Three days later, Eduardo Bolsonaro, the Brazilian president’s son, tweeted out a similar message, including an article that called the researchers “left-wing medical activists” and included their past social media posts in support of certain political candidates and sporting rainbow flag profile frames as proof. The article framed the study, which was later published in JAMA Network Open, as an attempt to “disparage the drug that the Bolsonaro government approved as effective for treating COVID-19.” Soon, death threats against the researchers and their families started to come in.

Then came the inquiry from the federal prosecutor’s office—the first such investigation of a medical study approved by an ethical review board, according to the research team’s lawyers. A Brazilian official announced the investigation on Twitter and posted a nine-page document that asked Lacerda’s team to justify everything from their choice of chloroquine to why the study didn’t focus on patients in earlier stages of COVID-19. Many of the questions centered on how the dose was determined and whether patients in the study experienced cardiac problems. The investigation is ongoing.

Brazilian researchers worry the legal inquiry from a federal prosecutor’s office could set a dangerous precedent in a nation already beset by attacks on science. “Today it’s [Lacerda], tomorrow it’s anyone else,” says Mauro Schechter, an infectious disease researcher at the Federal University of Rio de Janeiro, Rio de Janeiro. “It was quite outrageous the way things developed,” adds Adauto Castelo, an infectious disease researcher at the Federal University of São Paulo, São Paulo.
Tricky position

But there has been a real scientific debate about what an appropriate dose might be. Chloroquine is highly effective against malaria—unless resistance emerges—but test tube studies suggest much higher levels may be needed for the drug to block viruses. Both chloroquine and hydroxychloroquine are known to be toxic at high doses, but most information on toxicity comes from studies on suicides and accidental poisonings, where the dose was often not precisely known.

That put clinical researchers in a tricky position, White says. Go too low and you might miss the lifesaving activity of the drug. Go too high and you might endanger your patients.

Lacerda went very high. The 12 grams given to participants in his high-dose arm approached two times what was used in Recovery trial, which didn’t show a benefit from hydroxychloroquine, and in the World Health Organization’s Solidarity trial, which didn’t see a benefit either and ended its hydroxychloroquine arm on Wednesday. At least two hydroxychloroquine trials—one of 150 patients in Shanghai and a study at the University of Pennsylvania—went slightly over Lacerda’s total, but most studies used far less.

The participants in Lacerda’s trial were also given two to three other medications, including azithromycin, which shares chloroquine’s propensity to cause heart problems. It’s hard to evaluate just how harmful the high-chloroquine doses may have been, says James Watson of Mahidol University, who has attempted to model the toxicity of various dosing regimens.

“I’m sure that it’s going to be a very nice scientific discussion,” Lacerda says, adding that the criticisms of the high dose didn’t start until politics got involved. “Some people will be against that dose, some people will be in favor of that dose, and, unfortunately, I was the one who had the bad luck to be the first one to try the high dose. I probably will have to pay the price for that forever.”

White maintains Lacerda and his team made a reasonable choice at the time of their trial. But Kremsner says both Recovery and Lacerda’s trial were “a dangerous undertaking.” Two trials in Germany he leads—one in hospitalized patients and one in milder cases at home—use 3.3 grams over 7 days as the maximum dose . David Boulware of the University of Minnesota, Twin Cities, who led a study of hydroxychloroquine as a prophylactic drug in people exposed to the virus, says he wouldn’t be comfortable with Lacerda’s high dose either, but says the decision was “not crazy,” particularly given the “desperate times” of a pandemic without alternative treatment. (Boulware’s own study, which came up empty-handed, gave subjects 2.9 grams over 3 days.) “I think it would be reckless if they had no monitoring plan,” Boulware says. “There was a monitoring plan, they did stop the trial early, and they didn’t hide their results—they published them to try to warn others.”
Intense strain

Part of Lacerda’s problem is that he appeared unaware that the dose was very high. In the preprint, the team justified the high dose in part by pointing to an expert consensus coming from Guangdong province in China that recommended using 500 mg of chloroquine phosphate twice daily—seemingly in the same ballpark as the 600 mg the Brazilian team used. Lacerda also discussed the consensus in the New York Times story and again in a 20 April written statement defending his study.

But the comparison was off. A dose of chloroquine base, the nomenclature used by Lacerda, is 67% more potent than an equal dose of cloroquine phosphate, which the Chinese authors used. Lacerda said the mistake came when writing the preprint, after the trial was completed. He says the team did a wide literature review before making its dose decision and that the Guangdong dose was just one factor in their choice. Lacerda is still under intense strain from the fallout. “It’s a nightmare,” he told Science in a video call. For weeks he hasn’t been able to stop worrying that “my whole career is gone” or agonizing over the death threats against his family. “The day someone tells in your social media, that they’re going to kill your children to make you suffer the way you made other people suffer, you will understand what I’ve been through,” he says.

With reporting by Kai Kupferschmidt.
Posted in:
Health
Coronavirus

doi:10.1126/science.abd4620

Lindzi Wessel  is a writer based in Santiago, Chile.

ANIMAL EXPERIMENTATION

This shrimp has some of the fastest eyes on the planet


KINGSTON ET AL., BIOLOGY LETTERS

By Elizabeth PennisiJun. 23, 2020

Though not much bigger than a wooden match stick, snapping shrimp (Alpheus heterochaelis, pictured) are already famous for their loud, quick closing claws, the sound of which stuns their prey and rivals. Now, researchers have discovered these marine crustaceans have the eyesight to match this speed.

In the new study, scientists stuck a thin conducting wire into the eye of a chilled, live shrimp and recorded electrical impulses from the eye in response to flickering light. The crustaceans refresh their view 160 times a second, the team reports today in Biology Letters.
That’s one of the highest refresh rates of any animal on Earth. Pigeons come close, being able to sample their field of view 143 times per second, whereas humans top out at a relatively measly 60 times a second. Only some day-flying insects beat the snapping shrimp, the researchers report. As a result, what people—perhaps even Superman—and all other vertebrates see as a blur, the shrimp detects as discrete images moving across its field of vision.

Until a few years ago, most researchers assumed snapping shrimp didn’t see very well because they have a hard hood called a carapace that extends over their eyes. Although the hood seems transparent, with some coloration, it wasn’t clear how well it transmitted light. But it appears to be no impediment to the shrimp detecting fast moving prey or even predators whipping by. This might be important because the shrimp tend to live in cloudy water, so they don’t have much notice when another critter is approaching them.

Posted in:
Plants & Animals

doi:10.1126/science.abd4752

Lawsuit alleges scientific misconduct at U.S. nuclear weapons lab

Peter Williams claims tweaks to a program for modeling a bomb’s explosive trigger make its predictions unreliable. CLAUDIA WILLIAMS

By Adrian ChoJun. 24, 2020 ,

An unusual lawsuit alleges scientific misconduct at Lawrence Livermore National Laboratory in California, one of the United States’s three nuclear weapons labs. Peter Williams, a 50-year-old physicist, worked at Livermore from January 2016 until May 2017, when he says he was fired in retaliation for complaining that his superiors were mishandling a computer program that simulates the detonation of high explosives, undermining their ability to predict how a particular nuclear weapon would perform if used. Williams, who now works at a private research lab, has sued Livermore and seven individuals for reinstatement and $600,000 in damages.

Researchers familiar with the labs say Williams’s allegations should be taken seriously. “If there’s been a cover-up, that’s something that ought to be looked into,” says Raymond Jeanloz, a geophysicist at the University of California, Berkeley, who has been involved with the weapons labs. But he also says the labs implement internal reviews and other measures to ensure the integrity of their work and head off the kind of problem Williams alleges. “This is exactly the kind of thing the people at the lab worry about,” Jeanloz says. Livermore declined to comment on the suit, but in a statement said: “Rigorous debate is a part of the scientific process—the Laboratory does not retaliate against individuals for holding differing opinions.”

The suit, which Williams filed on 22 May, seems quixotic. He is representing himself; to make his case, he needs documents that only the lab can provide; and his complaint centers on a differential equation. Williams spent only a short time at Livermore before he was fired. (In a 12-month performance review Williams included in his suit, his superiors state he wasn’t keeping up with assignments.) Before joining the lab he did two postdocs, taught at City College of San Francisco and Sonoma State University, and worked for 8 years at Agilent Technologies. But Williams is a talented scientist, says Craig Wheeler, an astrophysicist at the University of Texas, Austin, who was his graduate adviser and has subsequently published with him. “He’s a deep, independent thinker,” Wheeler says. “He’s definitely not a crackpot.”

At Livermore, Williams was given the unclassified task of modeling the behavior of a high explosive. Called PBX 9502, the polymer-bonded explosive is intended to be used in refurbishing a 40-year-old thermonuclear warhead called the W80, which is about the size of a garbage can and fits on a cruise missile. The explosive, when detonated, would compress the warhead’s plutonium pit to set off a nuclear fission explosion, which in turn would trigger an even more powerful fusion explosion. Modeling a high explosive is difficult, researchers say, because its behavior depends on its density, which can vary from batch to batch and within a single piece. But such modeling is crucial to be sure that stored weapons will work as intended because the United States gave up nuclear testing in 1992 under the still unratified Comprehensive Nuclear-Test–Ban Treaty.

PBX 9502 is especially tricky because it’s an insensitive explosive, meaning it won’t go up if smacked or set on fire. But that also means that as the detonation front moves through the material, the chemical reactions behind it progress more slowly than in older explosives, Williams says. So instead of assuming the reactions are instantaneous, researchers must model their evolution, too.

To make sure they can do so correctly, researchers detonate samples of the stuff in different geometries, observe the explosions with ultra–high-speed cameras and other tools, and compare the results with simulations. For example, in one test, the sample resembles a mallet, with a thin cylindrical handle that leads to a fatter cylindrical head. Because the detonation front cannot instantly turn the corner where skinny cylinder meets fat, the explosion doesn’t consume the entire sample, but leaves a ring of material whose thickness reveals the speed of the detonation front and chemical reactions.

Livermore used such test explosions to refine a modeling program called ARES-CHEETAH. But Williams says he became aware that one of his supervisors was essentially changing parameters in the program after the fact to make sure the simulation fit the data from each experimental setup. That’s “pseudoscience,” Williams charges, as it guarantees the model will look accurate, even if it isn’t. He says he repeatedly asked the researcher to explain the rationale for the tweaking. “It became clear that he didn’t have a rationale, he had a motive,” Williams says. “And the motive was to keep money flowing to help develop and improve CHEETAH.”

Such “curve fitting” renders the program incapable of making meaningful predictions, he says. If CHEETAH can’t properly model the bench tests of PBX 9502, larger, far more expensive integrated test explosions of the weapon’s nonnuclear components could fail, he says. And modelers may not be able to correctly calculate the yield of the refurbished weapon, he says.

That would be a big problem, says Robert Rosner, a theoretical astrophysicist at the University of Chicago and former director of Argonne National Laboratory who is on Livermore’s advisory board. The uncertainty in the yields of various weapons directly affects calculations of how big the U.S. nuclear arsenal should be and could determine the course of future arms control negotiations, Rosner says. “The extent to which we can decrease [the stockpile] is completely related to the ability to be certain about the yield.”

But Rosner says he’s neither surprised nor alarmed to hear researchers had to adjust the high-explosives models to fit different experiments. What Williams sees as unacceptable tweaking is an inevitable part of the empirical modeling of any complex system, such as the climate or a star, Rosner says. “The idea that the model has to be tuned, I find that unsurprising,” he says. “I would be stunned if it didn’t.”

Both Rosner and Jeanloz say they suspect Williams may not know the whole story behind ARES-CHEETAH, as the lab dismissed him before he obtained a clearance to work on classified material. The weapons program also takes explicit measures to ensure that researchers adhere to scientific standards, Jeanloz says, such as running its own classified peer-reviewed journals and encouraging researchers to keep a hand in unclassified research. The rivalry between Livermore and Los Alamos National Laboratory in New Mexico provides a particularly valuable check, scientists say.

Yet Jeanloz and Rosner agree that models like CHEETAH need careful scrutiny. That’s because some policymakers may view uncertainties in modeling as a reason to resume nuclear testing. In fact, Jeanloz says, some arms control experts argue that to discourage calls for new tests, the United States should make no changes to its existing nuclear arms—even ones that make them safer, such as switching to insensitive explosives.

Williams does not yet have a court date. He’s suing, he says, not out of anger, but out of a sense of scientific duty: “I couldn’t look myself in the mirror if I didn’t do it.”
Posted in:
Science and Policy
Scientific Community

doi:10.1126/science.abd4839

Gravitational waves reveal lightest black hole ever observed


Ripples in space itself have revealed a merger of a large black hole with an object thought to be too small to be a black hole. N. FISCHER, S. OSSOKINE, H. PFEIFFER, AND A. BUONANNO/MAX PLANCK INSTITUTE FOR GRAVITATIONAL PHYSICS/SIMULATING EXTREME SPACETIMES COLLABORATION

By Adrian Cho Jun. 24, 2020 , 2:15 PM

Gravitational wave detectors have spotted a cosmic collision in which a giant black hole swallowed up a mystery object seemingly too heavy to be a neutron star, but too light to be a black hole. Weighing in at 2.6 times the mass of the Sun, the object falls into a hypothetical “mass gap,” a desert between the heaviest neutron star and the lightest black hole that some theories predict—suggesting the gap doesn’t exist and that those theories need to be amended.

“People who thought there was a mass gap will have to rethink it, for sure,” says Cole Miller, an astrophysicist at the University of Maryland, College Park, who was not involved in the observation. He adds, however, “People aren’t going to be joining cults because they cannot survive this change in their worldview.”

The data come from physicists working with the Laser Interferometer Gravitational-Wave Observatory (LIGO), a pair of detectors in Louisiana and Washington state, and Virgo, a similar detector in Italy. All three consist of huge, exquisitely sensitive optical instruments that can detect the fleeting stretching of space itself set off when two massive objects, such as black holes, swirl into each other. Since LIGO first sensed such gravitational waves in 2015, physicists have spotted dozens of mergers. And on 14 August 2019, the LIGO and Virgo detectors spotted a merger of objects with masses 23 and 2.6 times that of the Sun, the joint LIGO-Virgo collaboration announced yesterday.

It’s the 2.6–solar-mass object that raises eyebrows because it falls squarely in the mass gap, says Vicky Kalogera, an astrophysicist and LIGO team member from Northwestern University. “Now, for the first time, we have seen such an object,” she says. By sensing only the gravitational waves from the collision, LIGO and Virgo cannot tell for sure what the object is, she says. But nuclear physics suggests a neutron star heavier than about 2.2 solar masses cannot support its own weight, so the object is “almost certainly” a black hole, Miller says.

Yet it’s not easy to form a black hole this light, explains Feryal Özel, an astrophysicist at the University of Arizona. Prior to the advent of LIGO and Virgo, the only observational evidence for black holes came from the study of about 30 in our own galaxy, each of which orbits a companion star that feeds hot matter into it. None of these black holes weighs less than five solar masses, Ozel noted and colleagues noted in 2010. So they posited a mass gap between about 2.5 and five solar masses in which there should exist neither neutron stars nor black holes. But that notion rests on observation, Özel stresses. “Is there a fundamental physics reason black holes can’t form below five solar masses? We certainly don’t think so,” she says. “But, there must be something in the way massive stars evolve that makes it very hard.”

Subsequently, theorists explained why that may be so. Either a neutron star or a black hole can form when a massive star runs out of hydrogen fuel and its core begins to collapse. If the star is light enough, the core will collapse to a neutron star in a supernova explosion that blows away the rest of the star. If the star is too massive, however, its core will shrink to an infinitesimal point, leaving behind only its superintense gravitational field: a black hole. Theories suggest that, for these heavy stars, all but the outermost layers of the star fall in, boosting the black hole’s mass to five solar masses or more.

The new observation may put a dent in that theory—which Miller says has already met with some skepticism. “The supernova theorists who do the real modeling basically say, ‘Look, show us for sure there’s a mass gap and we’ll work on it,’” he says. And Özel, one of the original proponents of the mass gap, seems unperturbed by the find. “It’s very exciting,” she says. What’s more, LIGO and Virgo have shown that it’s possible to form a low-mass black hole in a different way. In August 2017, they spotted the merger of two neutron stars, which produced, presumably, a black hole of 2.7 solar masses.

The real puzzle may be the extreme mismatch in the masses of the black holes in the new observation, says Brian Metzger, a theoretical astrophysicist at Columbia University who was not involved in the work. Just a few weeks ago, LIGO and Virgo announced an event in which one black hole outweighed the other by a ratio of four to one. In the new event, the ratio is nine to one. “The interesting thing is the extreme mass ratio, which is hard to produce through most [models] people have focused on,” Metzger says.

Nobody knows how tightly orbiting pairs of black holes form in the first place. Most theorists have focused on two general scenarios, Metzger says: either orbiting pairs of stars that both collapse to form black holes or individual black holes that rattle around in tiny, old galaxies called globular clusters that somehow manage to pair up. Both scenarios tend to make pairs in which the black holes have similar masses. So theorists may have to dream up new hatcheries for lopsided black hole pairs, Metzger says, perhaps by starting in the dense centers of large galaxies.
Posted in:
Space

doi:10.1126/science.abd4841


Adrian Cho
Staff Writer

The chicken first crossed the road in Southeast Asia, ‘landmark’ gene study finds


The red jungle fowl's exotic plumage—and fierce fights among cocks—may have helped make the bird attractive to the early farmers who domesticated it. DAVID IRVING

By Andrew LawlerJun. 24, 2020 , 9:00 PM

It is the world’s most common farm animal as well as humanity’s largest single source of animal protein. Some 24 billion strong, it outnumbers all other birds by an order of magnitude. Yet for 2 centuries, biologists have struggled to explain how the chicken became the chicken.

Now, the first extensive study of the bird’s full genome concludes that people in northern Southeast Asia or southern China domesticated a colorful pheasant sometime after about 7500 B.C.E. Migrants and traders then carried the bird across Asia and on to every continent except Antarctica.

“Our results contradict previous claims that chickens were domesticated in northern China and the Indus Valley,” researchers led by Ming-Shan Wang from the Chinese Academy of Sciences’s Kunming Institute of Zoology write in a paper published today in Cell Research. They also found that the modern chicken’s chief ancestor is a subspecies of red jungle fowl named Gallus gallus spadiceus.
“This is obviously a landmark study,” says Dorian Fuller, an archaeologist at University College London who was not involved in the effort. He adds that the results could shed light on the emergence of agriculture and early trade networks, and what features of the bird made it so attractive to people.

Charles Darwin argued the chicken descended from the red jungle fowl because the birds resemble each other and can make fertile offspring; he speculated that domestication happened in India. But five varieties of the pheasant inhabit a broad arc extending from the jungles of Indonesia to the Himalayan foothills of Pakistan. Which variety led to the chicken, and where, was uncertain. Based on presumed chicken bones, archaeologists claimed, variously, that people domesticated the bird 9000 years ago in northern China and 4000 years ago in Pakistan.

DNA studies promised to resolve the issue, but researchers had few samples from the bird’s wild relatives. So Jianlin Han, a geneticist at the Joint Laboratory on Livestock and Forage Genetic Resources, embarked on a 20-year project to sample indigenous village chickens and wild jungle fowl near more than 120 villages across Asia and Africa.
Early bird

A subspecies of red jungle fowl (Gallus gallus spadiceus), found in northern Southeast Asia, likely led to the first domesticated chickens.


01000KmG. g. spadiceusNEPALINDIAMALAYSIAMYANMARLAOSTHAILANDCHINABANGLADESH
X. LIU/SCIENCE

Wang’s team sequenced the full genomes of 863 birds and compared them. The results suggest modern chickens descend primarily from domesticated and wild varieties in what is now Myanmar, Laos, Thailand, and southern China (see map, right). “This region is a center of domestication,” says co-author and geneticist Olivier Hanotte of the University of Nottingham. The results confirm a hypothesis put forward in 1994 by Japan’s Crown Prince Akishino, an ornithologist, on the basis of mitochondrial DNA data.

Wang’s team did find some evidence for a South Asian contribution: A jungle fowl native to the Indian subcontinent may have interbred with the chicken after its initial domestication in Southeast Asia, the team says.

The new DNA data link domesticated chickens most closely to the Southeast Asian subspecies G. g. spadiceus, however. They suggest the lineage that became the modern chicken branched off from the jungle fowl between 12,800 and 6200 years ago, with domestication occurring sometime after the lineages split.

Fuller doubts the bird was fully domesticated before the arrival of rice and millet farming in northern Southeast Asia about 4500 years ago. Hanotte acknowledges that “we need the help of archaeologists” to understand the human events that triggered domestication.

But Jonathan Kenoyer, an archaeologist and Indus expert at the University of Wisconsin, Madison, remains skeptical that the chicken arose in Southeast Asia. “They need to get ancient DNA” to back up their claims, he says, because genomes of modern birds may provide limited clues to early events in chicken evolution.

Nor does the DNA show what first enticed people to tame the bird. Early varieties were far scrawnier and produced fewer eggs than today’s industrial varieties, and their predators were legion. Some researchers suggest the bird was initially prized for its exotic plumage or for cockfighting. Selling prize fighting cocks remains a lucrative business in Southeast Asia, and the birds’ high value may have spurred traders to carry them long distances.

Smithsonian Institution archaeozoologist Melinda Zeder calls the new paper “fascinating” and says it shows “the domestication and dispersal story is more complicated than we thought.” She urges combining genetic and archaeological data to flesh out the tale. Archaeologists are now gathering chicken bones that suggest farmers in southern China and Southeast Asia first domesticated the bird some 3500 years ago—findings that bolster the genetic work.

Han’s group, meanwhile, is creating a massive data set based on more than 1500 modern chicken genomes from Asia, Europe, and Africa. The researchers plan to analyze chicken dispersal into Europe and Africa, as well as the genetic variations behind traits such as the ability to withstand disease or produce more eggs. “This study opens a whole new page in chicken genomics,” Han says.

Posted in:
Plants & Animals

doi:10.1126/science.abd4961

Andrew Lawler
Contributing Correspondent Andrew Lawler is based in Asheville, North Carolina. His most recent book is The Secret Token: Myth, Obsession, and the Search for the Lost Colony of Roanoke.